: CpG oligodeoxynucleotides (ODN) have immunomodulatory effects that may be useful for many future vaccine applications. The goal of this proposal is to understand how CpG ODN alter antigen processing and presentation of peptides to T cells. The project will also investigate how CpG ODN alter humoral immunity to polysaccharide Ags, as induced by immunization with either unconjugated PS or PS-protein conjugate vaccines. Aim 1: To determine the effect of CpG ODN on the ability of Ag presenting cells to process Ag and stimulate T cell responses to protein Ags. It is hypothesized that CpG ODN enhance Ag processing by dendritic cells and B cells. Investigators will determine the effects of CpG ODN on the ability of these cells to process and present exogenous protein Ags, including CRM 197, the carrier protein for glycoconjugate vaccines studied in Aims 2 and 3. Mechanisms for these effects will be explored, including the influence of CpG ODN on factors such as MHC-II synthesis and expression, half-life of peptide:MHC-II complexes, and expression of Ag processing components. Aim 2: To explore the adjuvant effects of CpG ODN on responses to PS and peptide epitopes of glycoconjugate vaccines, primarily using an experimental vaccine for Streptococcus pneumoniae. It is suggested that CpG ODN will enhance Ab responses to PS epitopes of glycoconjugate vaccines and alter the Ab isotypes that are elicited (e.g., to induce IgG2a and IgG3 responses in mice). The mechanisms of these effects will be determined including the roles of cytokines and T cells. Aim 3: Experiments will test whether CpG ODN can act as effective adjuvants in concert with vaccines containing only unconjugated PS immunogen to enhance PS-specific IgM and IgG1 responses and induce PS-specific Ab of other isotypes. Mechanisms of these effects will be determined (e.g., roles of T cells and cytokines). Understanding the modulation of Ag presenting cells by CpG ODN would increase our understanding of the basic mechanisms of adjuvant function for CpG ODN. The ability of CpG ODN to enhance humoral immunity to PS Ags would allow the development of improved vaccines for encapsulated bacteria.